Ao Duan, Zemeng Ma, Xiaolong Shao, Zhencheng Xiong, Chaoyi Zhang, Wenzheng Liu, Guanglin Wang, Shouye Hu, Wei Lin
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Specifically, the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>The effects of CBR-470-1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro-computed tomography imaging, Safranin-O and Fast Green staining, immunofluorescence staining and enzyme-linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co-culture system of THP-1 and chondrocytes was established to investigate the impact of CBR-470-1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte-related proteins within the system.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>In hypoxic conditions, CBR-470-1 significantly inhibited the progression of OA in the DMM-induced OA mouse model, but that effect disappeared in the DMM-induced OA phosphoglycerate kinase 1 (PGK1)<sup>fl/fl</sup>Lyz2-Cre mouse model. Not only that, CBR-470-1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte-related proteins in the co-culture system of THP-1 and chondrocytes.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>This study conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro-inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin-specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR-470-1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>Hypoxia plays a pro-inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3.</li>\n \n <li>Hypoxia plays a pro-inflammatory role by increasing PGK1 activity, reducing the binding of the deubiquitinating enzyme USP14 to NLRP3, and reducing the ubiquitination level of NLRP3.</li>\n \n <li>CBR-470-1 reverses the role of hypoxia in the progression of osteoarthritis.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680553/pdf/","citationCount":"0","resultStr":"{\"title\":\"The antiarthritic effect of CBR-470-1 in hypoxic environment is to increase the level of NOD-like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity\",\"authors\":\"Ao Duan, Zemeng Ma, Xiaolong Shao, Zhencheng Xiong, Chaoyi Zhang, Wenzheng Liu, Guanglin Wang, Shouye Hu, Wei Lin\",\"doi\":\"10.1002/ctm2.70118\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>The effects of CBR-470-1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro-computed tomography imaging, Safranin-O and Fast Green staining, immunofluorescence staining and enzyme-linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co-culture system of THP-1 and chondrocytes was established to investigate the impact of CBR-470-1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte-related proteins within the system.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>In hypoxic conditions, CBR-470-1 significantly inhibited the progression of OA in the DMM-induced OA mouse model, but that effect disappeared in the DMM-induced OA phosphoglycerate kinase 1 (PGK1)<sup>fl/fl</sup>Lyz2-Cre mouse model. Not only that, CBR-470-1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte-related proteins in the co-culture system of THP-1 and chondrocytes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>This study conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro-inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin-specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR-470-1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key points</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Hypoxia plays a pro-inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3.</li>\\n \\n <li>Hypoxia plays a pro-inflammatory role by increasing PGK1 activity, reducing the binding of the deubiquitinating enzyme USP14 to NLRP3, and reducing the ubiquitination level of NLRP3.</li>\\n \\n <li>CBR-470-1 reverses the role of hypoxia in the progression of osteoarthritis.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":10189,\"journal\":{\"name\":\"Clinical and Translational Medicine\",\"volume\":\"15 1\",\"pages\":\"\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2024-12-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11680553/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70118\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70118","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
The antiarthritic effect of CBR-470-1 in hypoxic environment is to increase the level of NOD-like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity
Background
Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA.
Methods
The effects of CBR-470-1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro-computed tomography imaging, Safranin-O and Fast Green staining, immunofluorescence staining and enzyme-linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co-culture system of THP-1 and chondrocytes was established to investigate the impact of CBR-470-1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte-related proteins within the system.
Results
In hypoxic conditions, CBR-470-1 significantly inhibited the progression of OA in the DMM-induced OA mouse model, but that effect disappeared in the DMM-induced OA phosphoglycerate kinase 1 (PGK1)fl/flLyz2-Cre mouse model. Not only that, CBR-470-1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte-related proteins in the co-culture system of THP-1 and chondrocytes.
Conclusions
This study conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro-inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin-specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR-470-1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment.
Key points
Hypoxia plays a pro-inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3.
Hypoxia plays a pro-inflammatory role by increasing PGK1 activity, reducing the binding of the deubiquitinating enzyme USP14 to NLRP3, and reducing the ubiquitination level of NLRP3.
CBR-470-1 reverses the role of hypoxia in the progression of osteoarthritis.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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